A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase

We previously reported the identification of a novel family of immunomodulatory proteins, termed helminth defense molecules (HDMs), that are secreted by medically important trematode parasites. Since HDMs share biochemical, structural, and functional characteristics with mammalian cathelicidin-like host defense peptides (HDPs), we proposed that HDMs modulate the immune response via molecular mimicry of host molecules. In the present study, we report the mechanism by which HDMs influence the function of macrophages. We show that the HDM secreted by Fasciola hepatica (FhHDM-1) binds to macrophage plasma membrane lipid rafts via selective interaction with phospholipids and/or cholesterol before being internalized by endocytosis. Following internalization, FhHDM-1 is rapidly processed by lysosomal cathepsin L to release a short C-terminal peptide (containing a conserved amphipathic helix that is a key to HDM function), which then prevents the acidification of the endolysosomal compartments by inhibiting vacuolar ATPase activity. The resulting endolysosomal alkalization impedes macrophage antigen processing and prevents the transport of peptides to the cell surface in conjunction with MHC class II for presentation to CD4(+) T cells. Thus, we have elucidated a novel mechanism by which helminth pathogens alter innate immune cell function to assist their survival in the host.-Robinson, M. W., Alvarado, R., To, J., Hutchinson, A. T., Dowdell, S. N., Lund, M., Turnbull, L., Whitchurch, C. B., O'Brien, B. A., Dalton, J. P., Donnelly, S. A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase.

Socio-economic deprivation and visual acuity at presentation in exudative age-related macular degeneration

Aim: To evaluate the influence of socio-economic factors on visual acuity (VA) at presentation in exudative age- related macular degeneration (AMD). Methods: The medical records of all consecutive patients with newly diagnosed exudative AMD examined at the Ophthalmology Departments of Grampian University Hospitals-NHS Trust, Aberdeen, and Gartnavel General Hospital, Glasgow, between July 2004 and June 2005, were reviewed. Demographics, duration of symptoms, VA in study and fellow eye, exudative AMD characteristics, status of fellow eye and patient home address, used to determine the Scottish Index of Multiple Deprivation (SIMD) score, were recorded. The effect of these parameters on VA at presentation was investigated using general linear modelling. Results: Two-hundred and forty patients (median age 79 years) were included in this study; 44 (18.3%) belonged to the lowest 20% SIMD score (most deprived). Age and location and type of the choroidal neovascular- isation were statistically significantly associated with VA at presentation (p = 0.003, p

Limbal stem cell deficiency:Concept, aetiology, clinical presentation, diagnosis and management

Defects in renewal and repair of ocular surface as a result of limbal stem cell deficiency are now known to cause varying ocular, surface morbidity including persistent photophobia, repeated and persistent surface breakdown and overt conjunctivalisation of the cornea. Ocular conditions with abnormalities of ocular surface repair include pterygium, limbal tumours, aniridia, severe scarring following burns, cicatricial pemphigoid and Stevens-Johnson Syndrome, sequelae of mustard gas exposure and Herpes simplex epithelial disease, radiation keratopathy, contact lens induced keratopathy, neuroparalytic keratitis and drug toxicity. Restoring ocular health in these eyes has traditionally been frustrating. An understanding of these intricate cell renewal and maintenance processes has spurred the evolution in recent years of new treatment methods for several blinding diseases of the anterior segment; many more exciting modalities are in the offing. However, there is inadequate awareness among ophthalmologists about the current principles of management of ocular surface disorders. The purpose of this article is to help elucidate the important principles and current treatment methods relevant to ocular surface disorders.

The effect of socio-economic deprivation on severity of glaucoma at presentation

OBJECTIVE: To evaluate the influence of socio-economic factors on severity of glaucoma at presentation

METHODS: All newly diagnosed glaucoma patients at the University Hospitals-NHS, Aberdeen and South Glasgow University Hospitals-NHS, in 2006, were included. Glaucoma was severe at presentation if there was a repeatable visual-field loss with a mean deviation index greater than 12 dB in the Humphreys visual fields test or an absolute paracentral scotoma within the central 5 degrees of the visual fields. Home address was used to determine the Scottish Index of Multiple Deprivation (SIMD) rank. The SIMD rank, demographics and severity of glaucoma at presentation were investigated using general linear modelling.

RESULTS: There were 48 patients with severe glaucoma and 74 patients with non-severe glaucoma. In four, the severity could not be determined. Severity of glaucoma at presentation was significantly associated with SIMD rank, being most severe in patients from areas with the lowest ranks (p = 0.026). Age was a significant factor (p = 0.024), with severe glaucoma being more common in elderly patients.

CONCLUSIONS: Age and socio-economic deprivation were associated with severity of glaucoma at presentation, with patients from areas of higher socio-economic deprivation presenting with more advanced glaucoma.

A curious case of hiccoughs - unusual presentation of eosinophilic granulomatosis with polyangiitis

We report a case of eosinophilic GPA (EGPA) presenting with persistent hiccoughs. The diagnosis was based on clinical and histological findings. Induction treatment with corticosteroids led to clinical improvement and rapid resolution of hiccoughs. Hiccoughing has never before been associated with acute EGPA and may reflect involvement of the phrenic and/or vagus nerves.

Processing of short auditory stimuli:The rapid audio sequential presentation paradigm (RASP)

Human listeners seem to be remarkably able to recognise acoustic sound sources based on timbre cues. Here we describe a psychophysical paradigm to estimate the time it takes to recognise a set of complex sounds differing only in timbre cues: both in terms of the minimum duration of the sounds and the inferred neural processing time. Listeners had to respond to the human voice while ignoring a set of distractors. All sounds were recorded from natural sources over the same pitch range and equalised to the same duration and power. In a first experiment, stimuli were gated in time with a raised-cosine window of variable duration and random onset time. A voice/non-voice (yes/no) task was used. Performance, as measured by d', remained above chance for the shortest sounds tested (2 ms); d's above 1 were observed for durations longer than or equal to 8 ms. Then, we constructed sequences of short sounds presented in rapid succession. Listeners were asked to report the presence of a single voice token that could occur at a random position within the sequence. This method is analogous to the "rapid sequential visual presentation" paradigm (RSVP), which has been used to evaluate neural processing time for images. For 500-ms sequences made of 32-ms and 16-ms sounds, d' remained above chance for presentation rates of up to 30 sounds per second. There was no effect of the pitch relation between successive sounds: identical for all sounds in the sequence or random for each sound. This implies that the task was not determined by streaming or forward masking, as both phenomena would predict better performance for the random pitch condition. Overall, the recognition of familiar sound categories such as the voice seems to be surprisingly fast, both in terms of the acoustic duration required and of the underlying neural time constants.